Genes causing two neurologic disorders with autosomal dominant inheritance have been mapped to human chromosome 9q bands 32-34 by genetic linkage studies: idiopathic torsion dystonia and tuberous sclerosis. Idiopathic torsion dystonia is a movement disorder characterized by twisting and repetitive movements or postures. Tuberous sclerosis (TSC) Is a multi-system disease whose manifestations include tubers or hamartomas in brain, kidney, and heart. The pathogenesis of these disorders is unknown. Strong linkage for early-onset Jewish and non-Jewish dystonia has been observed to the arginino-succinate synthetase (ASS) locus on 9q34. The disease gene is believed to lie In the 5 cM interval between the AK-1 and ASS loci. At least two loci exist for TSC, one of which, representing about 38% of affected families, is on 9q. This TSC disease gene is believed to lie in the 15 cM interval between AK-1 and ABO. Our long-term goal is to use a 'positional cloning' strategy to identify, without knowing their function, the genes causing these two disorders. To this end, I will determine a detailed genetic and physical map of 9q32-34, and identity new polymorphic DNA markers in this region. This will be accomplished by generation of radiation hybrid cell lines containing small regions of human chromosome 9q34 in a hamster background, using selection for the human ASS gene. I have already generated five such cell lines. These cell lines will serve as a resource for 1) identification of new polymorphic markers on 9q32-34 by Alu PCR and related techniques; 2) generation of a 'radiation sensitivity' map of 9q34; and 3) direct physical mapping by in-situ hybridization and pulse field gel analysis. New markers will be mapped by linkage analysis using reference pedigrees and applied to existing TSC and dystonia pedigrees. Markers will also be used to look for allele association with dystonia in the Jewish population, and for evidence of allele loss in lesions obtained from TSC patients. These approaches have great potential in further defining the site of the disease genes. These studies will result in tight localization of these disease genes and may make prenatal diagnosis and genetic counseling available to affected families. They will also provide a basis for the eventual identification of the disease genes, which will have broad importance for our understanding of the pathogenesis of these disorders and the development of specific therapies.